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1、主要内容,肝癌肝移植的疗效 肝癌肝移植的手术适应证选择 肝癌肝移植术后肿瘤复发的影响因素 肝癌肝移植术后肿瘤复发的预防 肝癌肝移植术后肿瘤复发的治疗,肝癌肝移植的疗效,中国大陆肝癌肝移植效果,我中心肝癌肝移植的结果,n=1717,我中心肝癌肝移植的结果,合并门静脉癌栓的肝癌,组（75例）：癌栓未累及门静脉主干 组（53例）：癌栓累及门静脉主干,郑虹，高伟，朱志军，等。 肝移植治疗肝细胞癌合并门静脉癌栓的疗效评价。中华器官移植杂志，2009，30：484-486。,伴淋巴结转移的肝癌,N=28,混合细胞型肝癌,（n=14）,陈洪磊，郑虹，王政禄，等。肝移植治疗混合细胞型肝癌14例。中国肿瘤临床，
2、2009，36：486-489,肝癌肝移植的手术适应证选择,肝癌肝移植的手术适应证,肝癌肝移植的手术适应证,关于Milan标准,1996年提出，5年存活率达70% 影像学检查对Milan标准的误诊率高达15%46% 很多超出Milan标准的患者可因肝脏移植获益,关于Milan标准,关于Milan标准,关于Milan标准,关于Milan标准,关于Milan标准,UCSF标准,2001年，California大学提出 单发肿瘤直径6.5cm 多发肿瘤3个，每个肿瘤直径4.5cm 肿瘤直径总和8cm 5年存活率达75%,Yao FY, Ferrell L, Bass NM, et al. Liver
3、 transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394 1403.,UCSF标准,Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded：A 22-year experience wi
4、th 467 patients at UCLA. Annals of Surgery, 2007, 246: 502-511.,UCSF标准,UCSF标准,Ju MK, Choi GH, Huh KH, et al. UCSF criteria by pre-transplant radiologic study can not assure similar post-transplant results of hepatocellular carcinoma within Milan criteria. Hepatogastroenterology. 2010 Jul-Aug;57(101)
5、:819-25.,UCSF标准,法国14个移植中心，459例患者 1985年至1998年 符合UCSF标准的患者5年生存率低于符合Milan标准的患者，但无统计学差异 5年生存率低于50%，不宜使用 UCSF报道5年无瘤生存率80%,Decaens T，Roudot-Thoraval F, Hadni-Bresson S, et al. Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waitin
6、g time. Liver Transpl. 2006 Dec;12(12):1761-9. Yao FY, Xiao L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant. 2007, 7(11):2587-96.,新Milan标准,Up-to-seven criteria 肿瘤最大直径与肿瘤个数之和不超过7 5年生存率达71.2%
7、,Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009; 10: 35.,肝癌肝移植的手术适应证 新Milan标准,Contour plot of the 5-year overall-survival probabili
8、ty according to size of the largest tumour, number of tumours, and presence or absence of microvascular invasion,新Milan标准,新Milan标准,无门静脉癌栓 肿瘤累计直径8 cm 术前AFP400 ngml 组织学分级为高中分化 n=195 5-y OS:70.7% 5-y DFS:62.4%,Transplantation , 2008, 85:1726-32,杭州标准,单发肿瘤直径9cm 多发肿瘤3个且每个5cm、所有肿瘤直径总和9cm 无大血管侵犯、淋巴结转移及肝外转移,
9、J Cancer Res Clin Oncol. 2009,N=1078,“上海复旦标准”（SHFD）,肝癌肝移植的手术适应证选择,如何选择手术适应证,目前的选择标准主要基于肿瘤形态学特点，如肿瘤大小，数目 肿瘤生物学行为对预后具有重要影响，如组织学分级，微血管侵犯 肿瘤形态学与生物学行为并不完全一致 因此，对肿瘤血清标记物、分子标记物、基因改变的研究成为热点,活体肝移植手术适应证,Lee SG, Hwang S, Moon DB, et al. Expanded indication criteria of living donor liver transplantation for hep
10、atocellular carcinoma at one large-volume center. Liver Transpl，2008; 14: 935. Ito T, Takada Y, Ueda M, et al. Expansion of selection criteria for patients with hepatocellular carcinoma in living donor liver transplantation. Liver Transpl 2007; 13: 1637. Sugawara Y, Tamura S, Makuuchi M. Living dono
11、r liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig Dis 2007; 25: 310.,如何选择活体肝移植手术适应证,活体肝移植供者存在一定的致病性（14%-21%）和致死性（0.25%-1%） 许多超出Milan标准的肝癌患者可因肝移植获益 活体肝移植器官来源具有定向性 多数学者认为，5年生存 率至少应50%,肝癌肝移植术后肿瘤复发 的影响因素,预后相关因素,TNM分期对预后的影响,Marsh JW, Dvorchik I, Bonham CA, et al. Is the p
12、athologic TNM staging system for patients with hepatoma predictive of outcome? Cancer 2000; 88(3):53843.,手术方式对预后的影响,Fishera RA, Kulikb LM, Freisec CE, et al. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. American Journal of Transplantation 2
13、007; 7: 16011608.,手术方式对预后的影响,Li C, Wen TF, Yan LN, et al. Outcome of hepatocellular carcinoma treated by liver transplantation: comparison of living donor and deceased donor transplantation. Hepatobiliary Pancreat Dis Int，2010, 9:366-369.,手术方式对预后的影响,Vakili K, Pomposelli JJ, Cheah YL, et al. Living D
14、onor Liver Transplantation for Hepatocellular Carcinoma: Increased Recurrence but Improved Survival Liver transplantation,2009,15:1861-1866.,手术方式对预后的影响,Hwang S, Lee SG, Ahn CS, et al. Small-sized liver graft does not increase the risk of hepatocellular carcinoma recurrence after living donor liver t
15、ransplantation. Transplantation Proceedings, 2007, 39:15261529.,手术方式对预后的影响,理论上讲，小体积移植物的缺血再灌注损伤和肝再生导致的血管生成可能促进肿瘤进展 但目前临床实际影响并不明确 目前临床证据表明，移植物类型对肝移植术后肿瘤进展并无或仅有轻微影响,等待时间对预后的影响,Chao SD, Roberts JP, Farr M, et al. Short waitlist time does not adversely impact outcome following liver transplantation for h
16、epatocellular carcinoma. American Journal of Transplantation 2007; 7: 15941600.,肝癌肝移植术后肿瘤 复发的预防,术 前 治 疗,术前治疗的目的 控制肿瘤生长和血管侵润 新辅助治疗减少患者移植术后复发风险 肿瘤降期，使移植成为可能,术前治疗TACE,No convincing arguments showing that TACE reduces the rate of drop out before LT No convincing arguments showing that TACE improves the
17、survival after LT Although TACE induced complete tumor necrosis in some patients,Belghiti J, Carr BI, Greig PD, et al. Treatment before Liver Transplantation for HCC. Annals of Surgical Oncology, 2008,15: 9931000.,术前治疗TACE,Downstaging of HCC by TACE is possible in one-third to one-half of LT candida
18、tes But these patients have higher dropout rates, higher recurrence rates There is no sufficient evidence that pretransplant TACE may delineate the possibility of expanding current selection criteria for OLT in patients with HCC,Belghiti J, Carr BI, Greig PD, et al. Treatment before Liver Transplant
19、ation for HCC. Annals of Surgical Oncology, 2008,15: 9931000.,术前治疗射频消融,Pretransplant RF ablation for HCC as a strategy to reduce dropout has been addressed in three studies there is no data demonstrating that RF improves the survival after LT,Belghiti J, Carr BI, Greig PD, et al. Treatment before Li
20、ver Transplantation for HCC. Annals of Surgical Oncology, 2008,15: 9931000.,术前治疗肝切除,合并HBV感染的肝癌患者，行肝切除后肿瘤复发，80%符合Milan标准，可行挽救性肝移植 合并HCV感染的肝癌患者，行肝切除后肿瘤复发，60%超出Milan标准,Poon RT, Fan ST, Lo CM, et al. long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patien
21、ts with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 2002; 235:37382. Chirica M, Durand F, Sommacale D, et al. Long-term outcome after resection for small HCC in patients with hepatitis C virus infection: arguments for a strategy of resection as a bridge
22、 to transplantation rather than salvage transplantation. Hepatology 2004; (suppl 4);40:162A.,术前治疗肝切除,优势 可以得到更多的病理学证据（如分化程度，有无微血管侵犯，有无卫星灶等），更有效的预测肝移植的预后并选择手术时机,术前治疗新辅助化疗,Soderdahl G, Backman, Isoniemi H, et al. A prospective, randomized, multi-centre trial of systemic adjuvant chemotherapy versus no
23、additional treatment in liver transplantation for hepatocellular arcinoma. European Society for Organ Transplantation, 2006 ,19: 288294.,TACE联合索拉菲尼,BMC Cancer 2008, 8:349 doi:10.1186/1471-2407-8-349,免疫抑制方案的选择,Toso C,Merani S, Bigam DL, et al. Sirolimus-based immunosuppression is associated with incr
24、eased survival after liver transplantation for hepatocellular carcinoma. Hepatology 2010;51:1237-1243.,免疫抑制方案的选择,Vivarelli M, Cucchetti A, Barba GL, et al. Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors. Ann Surg 2008;248: 857862.,免疫抑制方案的选择,Chinnakotla S, Davis GL, V
25、asani S, Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl,2009,15:1834-1842.,免疫抑制方案的选择,Hepatocellular carcinoma recurrencefree survival in recipients treated with sirolimus-based immunosuppression. Abbreviation: CNI, calcineurin inhibitor.,
26、Zimmerman MA, Trotter JF, Wachs et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl 2008,14:633-638.,免疫抑制方案的选择,Vivarelli M, Dazzi A, Zanello M, et al. Effect of different immunosuppressive schedules on recurrence-free survival after li
27、ver transplantation for hepatocellular carcinoma. Transplantation 2010;89: 227231.,免疫抑制方案的选择,免疫抑制方案的选择,肝癌肝移植术后肿瘤 复发的治疗,肿瘤复发后的生存率,Shin WY, Suh KS, Lee HW, et al. Prognostic factors affecting survival after recurrence in adult living donor liver transplantation for hepatocellular Carcinoma. Liver tran
28、splantation, 16:678-684, 2010.,肿瘤复发后生存的影响因素,Shin WY, Suh KS, Lee HW, et al. Prognostic factors affecting survival after recurrence in adult living donor liver transplantation for hepatocellular Carcinoma. Liver transplantation, 16:678-684, 2010.,治疗方法对预后的影响,Kornberg A, Kupper B, Tannapfel A, et al. L
29、ong-term survival after recurrent hepatocellular carcinoma in liver transplant patients: Clinical patterns and outcome variables. Eur J Surg Oncol. 2010;36(3):275-80.,全身化疗,Overall survival (OS) KaplanMeier curve (n = 24) in patients receiving palliative chemotherapy for recurrent hepatocellular carc
30、inoma after liver transplantation. Median OS was 16.6 weeks.,化疗副作用可以耐受 但疗效不满意,Lee JO, Kim DY, Lim JH, et al. Palliative chemotherapy for patients with recurrent hepatocellular carcinoma after liver transplantation. Journal of Gastroenterology and Hepatology, 2009, 24: 800805.,索拉菲尼治疗肝移植术后肿瘤复发,索拉菲尼治疗肝
31、移植术后肿瘤复发,Kim R, Aucejo F. Radiologic complete response with sirolimus and sorafenib in a hepatocellular carcinoma patient who relapsed after orthotopic liver transplantation. J Gastrointest Canc, 2010, Aug 18.,索拉菲尼治疗肝移植术后肿瘤复发,Bhoori S, ToffaninS, Sposito C, et al. Personalized molecular targeted the
32、rapy in advanced, recurrent hepatocellular carcinoma after liver transplantation:A proof of principle. Journal of Hepatology, 2010,52: 771775.,I125联合索拉菲尼治疗肺转移瘤,Li CX, Zhang FJ, Zhang WD, et al. Feasibility of 125I brachytherapy combined with sorafenib treatment in patients with multiple lung metasta
33、ses after liver transplantation for hepatocellular carcinoma. J Cancer Res Clin Oncol (2010) 136:16331640.,TACE联合索拉菲尼,Tan WF, Qiu ZQ, Yu Y, Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation. Acta Pharmacologica Sinica, 2010, 31: 16431648.,